A pivotal event in the pathogenesis of Type 2 diabetes mellitus (NIDDM) is the development of hepatic insulin resistance. Normal, or elevated glucose production, in the face of peripheral insulin resistance, results in the fasting hyperglycemia which is the hallmark of NIDDM. Our laboratory has been investigating the mechanism by which insulin restrains hepatic glucose output. The traditional view of this regulation is that insulin emanating from the pancreas has an immediate and direct effect to reduce HGO. However, by comparing portal and peripherally administered insulin, and carefully matching the doses, we have shown that the signal controlling the liver after carbohydrate feeding is generated from an extrahepatic tissue. We suggest that the rate limiting step for suppression of HGO is the transport of insulin across the endothelial barrier into adipose tissue. Lipolysis is suppressed, and the lowered free fatty acids (FFA) apparently signal the liver to reduce glucose output. The importance of this mechanism, the "single gateway hypothesis," will be examined in altered metabolic states including lengthy fasting, insulin resistance and experimental diabetes. The possibility that the single gateway mechanism is limited to regulation of gluconeogenesis, whereas there is a direct portal regulation of glycogenolysis will be studied. Also, considered will be the hypothesis that the mechanism by which FFA reduce HGO is by a direct effect on glucose-6 phosphatase, the final common pathway for hepatic glucose output. In additional studies, the specific role of FFA emanating from the omental circulation will be revealed. A test of the single gateway phenomenon will be whether specific antilipolytic compounds will reduce HGO independent of insulin. Finally, the antilipolytic compounds are administered directly into the artery perfusing the omental circulation. Obese animals will be prepared, and the hypothesis tested whether portal hyperlipemia, generated by direct omental infusion will result in the "insulin resistance syndrome (syndrome X)", with hyperinsulinemia, inappropriate lipid profile, and vascular alterations such as hypertension. This overall research program should yield important information regarding the physiological regulation of hepatic glucose production, and the role of those mechanisms in the pathogenesis of chronic disease.